Surface charge control of electropermeabilization and glycophorin electroinsertion with 1,2-diacyl-sn-glycero-3-phosphocholine (lecithin) liposomes

beta-Carotene has been studied widely as a potential cancer-preventing agent. Recent studies found that subjects who took beta-carotene supplements orally had increases in their serum concentrations of alpha-carotene and lycopene that were large (> 150% increase) and significantly greater than such increases in subjects who received placebo and that similar supplementation was associated with a decrease of approximately 37% in plasma lutein concentrations. A biologic interaction between beta-carotene and other carotenoids was suggested. We measured concentrations of retinol, alpha-tocopherol, and five carotenoids in serum specimens from a random sample of subjects enrolled in a clinical trial of the use of antioxidant vitamins in preventing colonic adenomas. We used serum specimens obtained at enrollment and after the subjects took placebo (n = 54) or 25 mg beta-carotene/d (n = 54) orally for 4 y. In a multivariate analysis, baseline serum concentrations of the analytes, sex, body mass index, diet, smoking status, and age were associated with variable changes in some analytes over the 4-y period but supplementation with beta-carotene was related only to a mean increase in serum beta-carotene itself of 151%. We excluded with 95% confidence an increase in lycopene > 4.9%, an increase in alpha-carotene > 17.6%, and a decrease in lutein > 14.7% in subjects given beta-carotene. These results confirm previous findings that supplementation with beta-carotene given orally does not alter serum concentrations of retinol or alpha-tocopherol. The findings also indicate that beta-carotene supplementation, which results in a moderate increase in serum beta-carotene concentration, does not significantly change serum concentrations of other carotenoids.     

Low and high responders to pharmacological doses of beta-carotene: proportion in the population, mechanisms involved and consequences on beta-carotene metabolism

The aim of this study was to assess the interindividual variability of chylomicron beta-carotene response to a pharmacological load of beta-carotene in the population, to identify the mechanisms responsible for this variability, and to evaluate its consequences on beta-carotene status and metabolism. The variability, as estimated by the 3-h chylomicron beta-carotene response to 120 mg beta-carotene in 79 healthy male volunteers, was high (CV = 61%), but it was unimodal and all the subjects had detectable chylomicron beta-carotene. In 16 subjects randomly selected among the 79, the interindividual variability of the triglyceride-adjusted chylomicron (beta-carotene + retinyl palmitate) response (0-12.5 h area under the curve) was high (CV = 54%), suggesting that there is a high interindividual variability in the efficiency of intestinal absorption of beta-carotene. The chylomicron beta-carotene response was correlated (r = 0.50, P < 0.05) with the chylomicron triglyceride response. The beta-carotene status, as assessed by beta-carotene concentration in buccal mucosal cells, was correlated (r = 0.73, P < 0.05) with the triglyceride-adjusted chylomicron beta-carotene response, i.e., with the ability to respond to beta-carotene. The triglyceride-adjusted chylomicron retinyl-palmitate response was correlated (r = 0.55, P < 0.05) with the triglyceride-adjusted chylomicron beta-carotene response. Plasma all-trans retinoic acid slightly, but significantly, increased (+40%) 3 h after the beta-carotene load, but this increase was not related to the triglyceride-adjusted beta-carotene response. In conclusion, the ability to respond to beta-carotene is highly variable, but there is probably a very small proportion of true non-responders to pharmacological doses of beta-carotene in the healthy population. This variability is apparently mainly due to interindividual differences in the efficiency of intestinal absorption of beta-carotene and in chylomicron metabolism. The ability to respond to beta-carotene can affect the beta-carotene status and the provitamin A activity of beta-carotene, but it has apparently no effect on the amount of retinoic acid appearing in the plasma after the ingestion of a pharmacological dose of beta-carotene.     

Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction

BACKGROUND: Epidemiological data suggest that the intake of antioxidants such as alpha-tocopherol (vitamin E) and beta-carotene has an inverse correlation with the incidence of coronary heart disease. The results from clinical trials of antioxidant supplementation in people with known coronary heart disease are inconclusive. METHODS: We studied the frequency of major coronary events in 1862 men enrolled in the alpha-tocopherol beta-carotene Cancer Prevention Study (smokers aged between 50 and 69 years) who had a previous myocardial infarction. In this randomised, double-blind. placebo-controlled study, men had received dietary supplements of alpha-tocopherol (50 mg/day), beta-carotene (20 mg/day), both, or placebo. The median follow-up was 5.3 years. The endpoint of this substudy was the first major coronary event after randomisation. Analyses were by intention to treat. FINDINGS: 424 major coronary events (non-fatal myocardial infarction and fatal coronary heart disease) occurred during follow-up. There were no significant differences in the number of major coronary events between any supplementation group and the placebo group (alpha-tocopherol 94/466; beta-carotene 113/461; alpha-tocopherol and beta-carotene 123/497; placebo 94/438 [log-rank test, p = 0.25]). There were significantly more deaths from fatal coronary heart disease in the beta-carotene (74/461, multivariate-adjusted relative risk 1.75 [95% CI 1.16-2.64], p = 0.007) and combined alpha-tocopherol and beta-carotene groups (67/497, relative risk 1.58 [1.05-2.40], p = 0.03) than in the placebo group (39/438), but there was no significant increase in the alpha-tocopherol supplementation group (54/466, relative risk 1.33 [0.86-2.05], p = 0.20). INTERPRETATION: The proportion of major coronary events in men with a previous myocardial infarction who smoke was not decreased with either alpha-tocopherol or beta-carotene supplements. In fact, the risk of fatal coronary heart disease increased in the groups that received either beta-carotene or the combination of alpha-tocopherol and beta-carotene; there was a non-significant trend of increased deaths in the alpha-tocopherol group. We do not recommend the use of alpha-tocopherol or beta-carotene supplements in this group of patients.     

Beta-carotene in HIV infection: an extended evaluation

OBJECTIVE: Several small short-term intervention studies have suggested that beta-carotene supplementation in HIV-infected patients can increase the number of various immune cells including CD4 cells. This prospective double-blinded study was designed to investigate whether beta-carotene supplementation would result in this immuno-enhancement in a larger number of patients over a longer time period. METHODS: HIV-positive patients were randomly assigned to receive either 60 mg beta-carotene orally three times daily or a matched placebo. In addition, all patients received a multivitamin supplement. Patients were evaluated at baseline, 1 month, and 3 months for T-cell quantitative subsets, natural killer cells, HIV p24 antigen, beta-carotene levels, complete blood counts and chemistry batteries. Body weights and Karnofsky scores were evaluated at each visit. RESULTS: Seventy-two patients signed informed consent forms and entered the study. Except for serum beta-carotene concentration, there were no statistically significant differences (P < 0.05) between the treatment (60 mg beta-carotene three times daily and multivitamins) and placebo (placebo and multivitamins) groups at baseline or after either 1 or 3 months of treatment. DISCUSSION: Earlier studies suggesting that beta-carotene supplementation increased levels of immune cells in HIV-infected patients were not replicated in this study. The addition of a multivitamin supplement to both arms of this study may have masked any difference between the two groups. However, on the basis of the results of this study, we would not recommend supplementation with high doses of beta-carotene for HIV-infected patients.     

Residual pressor effects of chronic alcohol in detoxified alcoholics

In a previous study we reported that beta-carotene solubilized in tetrahydrofuran (THF) is toxic for human colonic tumor cells in vitro using media containing 10% fetal calf serum (FCS). Cytotoxicity was evident using beta-carotene concentrations that are achieved in human serum as a result of supplementation with 30 mg beta-carotene/day. In an attempt to determine the mechanism for this toxicity we investigated the effect of beta-carotene when present in human serum as a result of dietary supplementation. This effect was compared to that observed for cells incubated in THF-solubilized beta-carotene. The results indicate that human serum from subjects with a high concentration of beta-carotene is not cytotoxic. Subsequent analysis revealed that in contrast to the results using FCS, THF-solubilized beta-carotene is not cytotoxic in the presence of human serum. In addition, the effect observed with FCS is blunted with increasing FCS concentration from > or = 90% cytotoxicity using 10% FCS to 36% using 100% FCS. The difference in results obtained using FCS and human serum may be due to a serum component that is relatively lacking in FCS as compared to human serum.     

Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial

To determine the impact of a trace element and vitamin supplementation on infectious morbidity, a double-blind controlled trial was performed on 81 elderly subjects in a geriatric center during a 2-year period. Subjects were randomly assigned to one of four treatment groups, and received daily: placebo; trace elements/zinc 20 mg; selenium 100 micrograms); vitamins (vitamin C 120 mg; beta-carotene 6 mg; alpha-tocopherol 15 mg); or a combination of trace elements and vitamins at equal doses. (1) Before supplementation, low serum values in vitamin C, folate, zinc and selenium were observed in more than two thirds of the patients. (2) After 6 months of supplementation, a significant increase in vitamin and trace element serum levels was obtained in the corresponding treatment groups: a plateau was then observed for the whole study. (3) Subjects who received trace elements (zinc and selenium) alone or associated with vitamins had significantly less infectious events during the 2 years of supplementation. These results indicate that supplementation with low doses of vitamins and trace elements is able to rapidly correct corresponding deficiencies in the institutionalized elderly. Moreover, zinc and selenium reduced infectious events.     

Enhanced plasma level of lipid peroxidation in Iranians could be improved by antioxidants supplementation

OBJECTIVE: To study the influence of supplementation with antioxidants on factors, which might increase the risk of coronary heart disease (CHD) in Iranians. DESIGN: Twenty-one male volunteers enter the prospective, single-blind, randomized study. SETTING: The supplementation was conducted at the Cardiovascular Center, University of Tehran, the biochemical analysis were carried out in the University of Graz. SUBJECTS: Twenty-one male medical students were recruited by advertisement. Five subjects were dropped out due to lack of the compliance. METHODS: One group of Iranians received 30 mg/d beta-carotene and placebo for alpha-tocopherol; the other received beta-carotene plus 400 IU alpha-tocopherol for ten weeks. Concentrations of antioxidants in plasma and low density lipoproteins (LDL), plasma lipid profile, autoantibody against oxidized LDL (oLAb) and malondialdehyde (MDA) concentrations in plasma were measured. Oxidative resistance of LDL was estimated using conjugated diene assay. RESULTS: Iranians had a significantly lower plasma levels of total cholesterol (P < 0.002), LDL-cholesterol (P < 0.01) and high density lipoprotein-cholesterol (P < 0.002), compared to healthy Austrian subjects (n = 13). Although the baseline concentrations of alpha-tocopherol and beta-carotene were comparable with Austrians, lycopene, canthaxanthin and lutein were significantly higher in Iranians (P < 0.03-0.001). In vitro oxidative resistance of LDL, measured as lag-time, was slightly higher (P < 0.01) in Iranians comparing with Austrians. Plasma MDA and oLAb concentrations were significantly higher in Iranians (P < 0.001). Both dietary supplementations reduced plasma MDA concentrations (P < 0.001-0.001). A key finding was that a supplement combined with alpha-tocopherol caused also a significant increase of oLAb concentration (P > 0.01) as well as the significant increase of lag-time (P > 0.005). CONCLUSIONS: This study shows that high plasma MDA level of Iranians can be decreased by beta-carotene supplementation with or without alpha-tocopherol. However, alpha-tocopherol is a more powerful antioxidant, which can increase the resistance of LDL to oxidation, reduce the MDA concentrations in plasma and increase autoantibodies to oLDL.     

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.     

Effect of beta-carotene supplementation on serum alpha-tocopherol concentration

Conflicting reports of the effects of beta-carotene supplementation on serum alpha-tocopherol concentration led us to evaluated serum alpha-tocopherol in subjects with and without beta-carotene (30 mg/day) supplementation for up to 2 years duration in an ongoing chemoprevention trial. No adverse effect has been observed at any of the time periods examined.     

Effect of chrysotile-asbestos and zeolites dust on generations of reactive oxygen species by alveolar macrophages and granulocytes

OBJECTIVE: To evaluate the discrepancy index between the clinical and histological diagnosis and the prevalence of epithelial dysplasia and carcinoma in 45 patients with potentially malignant epithelial oral lesions (PMEL). PATIENTS AND METHODS: We submitted 45 patients with PMEL to clinical examination and obtained a biopsy from each. The results of histological diagnosis were compared to the clinical diagnosis. RESULTS: Clinical diagnosis showed that the most common PMEL was leukoplakia followed by lichen planus and by actinic cheilitis associated with leukoplakia. The most common site was the buccal mucosa. Histological diagnosis revealed that 46.7% of the PMEL were lichen planus. The discrepancy index between clinical and histological diagnosis was 24.4%. The higher discrepancy index occurred among leukoplakias. The prevalence of epithelial dysplasia and carcinoma was 17.8%. CONCLUSIONS: We conclude that all PMEL should be submitted to a microscopic analysis because the discrepancy between clinical and histological diagnosis was present in a quarter of these lesions. Otherwise, the epithelial dysplasia and carcinoma were more frequent in the leukoplakias.     

Effects of organophosphorus, carbamate, pyrethroid and organochlorine pesticides, and a heavy metal on survival and cholinesterase activity of Chironomus riparius Meigen

BACKGROUND & AIMS: The first therapeutic experiences with the conventional photosensitizer dihematoporphyrinester in the treatment of Barrett's esophagus show the curative potential of photodynamic therapy (PDT). The aim of this study was to test 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX, a photosensitizer with a high mucosa specificity without phototoxic side effects on the skin, as a new form of PDT. METHODS: Thirty-two patients (mean age, 68.5 years) with histologically proven high-grade dysplasia (n = 10) and mucosal cancer (n = 22) in Barrett's esophagus were treated. Four to 6 hours after oral ingestion of 5-ALA (dose, 60 mg/kg body wt), irradiation was conducted with a dye laser system (635 nm) with a light dose of 150 J/cm2. The patients received 20-80 mg omeprazole daily after PDT. RESULTS: High-grade dysplasia was eradicated in all patients (10 of 10), and mucosal cancer was eliminated in 17 of 22 patients (77%) at a mean follow-up of 9.9 months (range, 1-30 months). All tumors < or = 2 mm in thickness were completely ablated (17 of 17). The method-related mortality and morbidity was 0%. CONCLUSIONS: Severe dysplasia and thin (< or = 2 mm) mucosal cancer of Barrett's esophagus can be completely ablated. PDT might offer a minimally invasive treatment modality as an alternative to esophagectomy.     

Pregnancy-related changes of carnitine and acylcarnitine concentrations of plasma and erythrocytes

The effect of beta-carotene on the susceptibility of low density lipoprotein (LDL) to oxidative modification was investigated in a double-blind, randomized placebo-controlled study. Hypercholesterolaemic, postmenopausal women were given 30 mg beta-carotene per day (n = 15 subjects) or placebo capsules (n = 15 subjects) for 10 weeks. They were instructed to follow the American Heart Association Step One diet. LDL, isolated before and after treatment was subjected to copper-catalysed lipid peroxidation. There were no significant differences between LDL from the beta-carotene and placebo groups, as assessed by measuring the lag time for formation of conjugated dienes; the rate of formation and the amount of conjugated dienes formed; the amount of lipid peroxides generated; and the relative electrophoretic mobility, at baseline and after treatment. Dietary records showed that the subjects were consuming similar amounts and types of fat. No significant differences were found in the lipid composition and fatty acid pattern of LDL from the two groups. In conclusion, the results indicated that supplementation with beta-carotene in non-smoking, hypercholesterolaemic, postmenopausal women had no protective effect on the susceptibility of LDL to copper-catalysed modification in vitro.     

Morphological classification of oral leukoplakia (author's transl)

656 cases of oral leukoplakia were analysed according to macroscopic aspects, microscopic growth patterns and histologicalcytological differentiation, and the relationship to cancer of the oral cavity was studied. Homogeneous and speckled leukoplakia can be distinguished macroscopically, while flat (70%), papillary-endophytic (22%) and papillomatous-exophytic (8%) types can be distinguished by their growth pattern. Histological-cytological characteristics consist of epithelial hyperplasia (hyperkeratosis with ortho- or parakeratosis; akanthosis) and epithelial dysplasia (dyskeratosis, basal-cell hyperplasia, loss of polar arrangement of the basal cells, cell polymorphism, increased mitosis rate). No or little dysplasia was demonstrated in 74% of leukoplakias, moderate in 17% and marked in 6%. Carcinoma-in-situ, defined as high-grade dysplasia with additional loss of epithelial layering, was found in 3%. Precancerous leukoplakia (in almost 10% of cases, counting high-grade dysplasias and carcinoma-in-situ) must be delineated as a special group. Numerous correlations were found between dysplastic leukoplakias and oral cavity cancer as regards localisation, age and sex distribution. In the various leukoplakia forms there was an increased incidence of marked stroma reactions and of Candida colonisation with increased degrees of dysplasia.     

Quantitation of vitamin E and a carotenoid pigment in cataractous human lenses, and the effect of a dietary supplement

The quantitation of tocopherols and carotenoids in lipid extracts of cataractous human lenses was performed in parallel with those of matched samples of plasma, which was also analysed at the same time. Alpha-tocopherol in cataractous lenses from elderly human subjects was present at 4.4 mumoles/kg wet weight, much less than the mean of 33 mumoles/l in plasma from these subjects. The mean ratio of alpha- and gamma-tocopherols was 3.5 in the lenses, and 11.3 in plasma. Lens extracts contained no detectable alpha- or beta-carotene, lycopene, or beta-cryptoxanthin. However, all the lens extracts contained a pigment with the retention time and spectrum of lutein and zeaxanthin. Using the molar extinction coefficient of lutein this was present at ca. 0.03 microM, compared with 0.2 microM in plasma. Seven patients with bilateral cataracts had one of their cataractous lenses removed and analysed, and were then given either an oral placebo, or an oral supplement of ascorbate, alpha-tocopherol and beta-carotene. Three months later, the second cataractous lens, and a blood sample, were analysed. Three of the seven had received the active supplement, as confirmed by substantially raised blood levels of alpha-tocopherol and beta-carotene, and raised aqueous humour levels of vitamin C. However, lens tocopherol levels remained unchanged, and no beta-carotene could be detected in the lenses after supplementation. This preliminary evidence needs to be confirmed in larger studies.     

Effect of oral beta-carotene supplementation on plasma human immunodeficiency virus (HIV) RNA levels and CD4+ cell counts in HIV-infected patients

We conducted a pilot, open-label study to assess the effect of short-term beta-carotene administration (180 mg/d with meals for 4 weeks) on the plasma human immunodeficiency virus (HIV) RNA levels and CD4+ lymphocyte counts in 21 HIV-infected patients. We found that plasma HIV RNA levels and CD4+ lymphocyte counts did not change following this short course of beta-carotene supplementation. Patients with lower serum concentrations of beta-carotene before supplementation were no more likely to have an increase in their CD4+ lymphocyte count or plasma HIV RNA copy number than were those with higher concentrations. No correlation was found between pre- or postsupplementation beta-carotene or vitamin A concentrations and pre- or postsupplementation CD4+ lymphocyte counts or plasma HIV RNA titers. This study provides no support for beta-carotene supplementation for HIV-infected subjects with normal baseline serum levels of beta-carotene and vitamin A.     

A high prevalence of p53 mutations in pre-malignant oral erythroplakia

Oral squamous-cell carcinoma is thought to be preceded by a number of precursor stages which induce morphological changes in cells of the oral mucosa resulting in clinically detectable pre-malignant lesions such as erythroplakia or leukoplakia. To better understand the etiology of oral erythroplakia, we have examined the p53 tumor-suppressor gene (exons 5-9) for mutations in 24 oral erythroplakia lesions of varying dysplastic phenotypes by PCR/single-strand conformational polymorphism and direct DNA-sequencing analyses. A total of 12 p53 mutations were detected in 11 of 24 (46%) erythroplakia specimens (one specimen contained two different p53 mutations); 25% were single-base-pair deletions and 33% were either G:C-->T:A transversions or G:C-->A:T transitions. A high prevalence of p53 mutation was observed in all categories of erythroplakia lesions: 33% for mildly dysplastic lesions, 50% for lesions exhibiting moderate to severe dysplasia and 50% for lesions that were carcinoma in situ. Although the combined prevalence of p53 mutations observed in erythroplakia was significantly higher (p = 0.02) than that observed earlier for leukoplakia, the prevalence of p53 mutations was similar in erythroplakia and leukoplakia specimens from smokers. The prevalence and spectrum of p53 mutations observed in this series of erythroplakia lesions are similar to those observed for oral squamous-cell carcinoma. These results indicate that mutations of the p53 gene may be linked to the high malignant potential of erythroplakia and provide further evidence that p53 mutation may be an early event in the genesis of oral squamous-cell carcinoma.     

Live attenuated SIV vaccines are not effective in a postexposure vaccination model

We examined the immunohistochemical expression of proliferating-cell nuclear antigen (PCNA) and p53 proteins in dysplasia and intramucosal carcinoma of the esophagus. Immunohistochemistry was performed with monoclonal antibodies directed against PCNA and p53. We used surgically resected specimens from 29 patients who had a total of 55 lesions of severe dysplasia (n = 16), intraepithelial carcinoma (n = 21), and mucosal carcinoma (n = 18). The mean PCNA index with immunoreactivity for p53 was 48.9 +/- 6.5 in areas of severe dysplasia (n = 7), 58.2 +/- 7.3 in areas of intraepithelial carcinoma (n = 10), and 71.4 +/- 9.3 in the invasive areas of mucosal carcinoma (n = 10). The mean PCNA index without immunoreactivity for p53 was 41.2 +/- 5.5 in areas of severe dysplasia (n = 9), 48.0 +/- 7.4 in areas of intraepithelial carcinoma (n = 11), and 63.7 +/- 9.1 in invasive areas of mucosal carcinoma (n = 8). The PCNA indices of the areas of severe dysplasia with immunoreactivity for p53 were significantly lower than those of intraepithelial carcinoma and mucosal carcinoma with immunoreactivity for p53. Similarly, the PCNA indices of severe dysplasia without immunoreactivity for p53 were significantly lower than those of intraepithelial carcinoma and mucosal carcinoma without immunoreactivity for p53. These results thus suggest that severe dysplasia has a lower proliferative potential than carcinoma and may therefore represent a precancerous lesion.     

Carotenoids and antioxidant vitamins in patients after burn injury

Oxidative stress may contribute to secondary tissue damage and impaired immune function in patients after burn injury. The purpose of our study was to describe plasma antioxidant micronutrient concentrations in 26 adult patients admitted with extensive burn injuries (> 20 % total burn surface area) to a level-1 trauma burn center during a 21-day period after admission. The effect of administering beta-carotene was also examined with use of a prospective randomized subjects design: patients received either placebo or 30 mg/day in an enteral feeding. Plasma concentrations of alpha- and gamma-tocopherol, carotenoids (alpha and beta-carotene, lycopene, beta-cryptoxanthin, lutein), and retinol were measured with high- performance liquid chromatography, and vitamin C was quantified with spectrophotometry, at baseline and twice per week. Vitamin C, tocopherol, and retinol concentrations were low at baseline, but levels increased significantly over the study period in both groups (p < 0.05). Plasma beta-carotene concentration increased when this carotenoid was provided in the oral feeding. Otherwise, plasma carotenoid concentrations were low at baseline and remained low throughout the study period despite normalization of associated lipids.     

Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers

OBJECTIVE: Repaglinide is a novel prandial glucose regulator (PGR) for the treatment of type 2 diabetes. In order to investigate subject variability following oral administration of repaglinide, and to determine the relative and absolute bioavailabilities of repaglinide following oral or intravenous administration, two single-centre, open-label, randomized, crossover clinical studies were conducted. SUBJECTS AND METHODS: Study 1 was conducted in 24 healthy male subjects (aged 18 to 49 years), who received repaglinide 2 mg, as either tablet or oral solution, twice each on 4 separate occasions at least 7 days apart. Study 2 was conducted in 12 healthy male subjects (aged 18 to 45 years), who received repaglinide 2 mg, either as a tablet or as an intravenous infusion over 15 minutes, once each on 2 separate occasions, with a washout period of 7-10 days. RESULTS: In study 1 there was no significant difference between administration of repaglinide 2 mg, in either tablet or oral solution form with regard to intrasubject variation in AUC and Cmax. However, the intrasubject variation in t(max) and mean residence time (MRT) was significantly (p = 0.001) larger for the tablets than for the oral solution. Intersubject variation (CV) in AUC ranged from 44.7% to 62.1% after oral administration. The relative bioavailability of repaglinide (AUC(tablet)/AUC(oral solution)) was 110% (95% CI, 103%-117%). In study 2 the absolute bioavailability of repaglinide administered as a tablet was 62.5% (95% CI, 49.2%-79.5%) relative to an intravenous infusion of the same dose. CONCLUSION: There was no evidence from either study that the tablet formulation led to greater variation in serum profiles of repaglinide. It was concluded that repaglinide is rapidly absorbed and eliminated in healthy subjects when administered orally or intravenously under fasting conditions, and that the total availability of repaglinide is similar in the tablet and oral solution formulations, though that the rate of absorption is slower for the tablet formulation.     

Corticosteroid therapy augments gastroduodenal permeability to sucrose

OBJECTIVE: The aim of the present study was to investigate whether corticosteroid therapy alters gastroduodenal mucosal permeability and whether permeability alteration is associated with macroscopic mucosal damage. METHODS: Eight patients taking oral corticosteroid therapy (total prednisone-equivalent dose, 1.5+/-0.1 g; duration, approximately 30 days), nine patients with multiple sclerosis taking high-dose intravenous methyl-prednisolone therapy (total dose, 11.7+/-0.5 g; duration, approximately 9 days), and 20 age- and gender-matched controls were studied. Gastroduodenal permeability was determined using sucrose as a site-specific permeability probe. Five-hour urine was collected after ingesting 100 g of sucrose and its urinary excretion rate was measured using high-pressure liquid chromatography. Gastroduodenal endoscopy was performed before steroid therapy to exclude subjects with evidence of macroscopic mucosal lesions. The sucrose test and endoscopy were repeated after completion of corticosteroid therapy. RESULTS: The urinary sucrose excretion rates were similar in the control group and in patient groups before corticosteroid therapy. The median excretion rate of sucrose increased four (one to 28)- and eight (two to 35)-fold, respectively, as compared with pretreatment values in patients taking oral steroid and high-dose intravenous methyl-prednisolone therapy (p < 0.01). Considering all patients together, subjects who received a mean prednisone-equivalent dose of 8.4+/-1.5 g exhibited mucosal lesions, whereas patients who received 3.3+/-1.8 g did not (p = 0.06). The post-therapy increments in sucrose excretion rates were associated with neither the presence of macroscopic lesions nor with the total steroid dose received. CONCLUSIONS: Corticosteroid therapy augments gastroduodenal permeability and high doses are associated with macroscopic mucosal lesions. Steroid-induced permeability increase does not appear to be associated with the presence of macroscopic mucosal lesions.